Synthetic derivatives of delta/9-THC are known to have certain therapeutic effects, including relief from pain, diminished nausea and vomiting due to cancer chemotherapies, and decreased ocular pressure in glaucoma. However, to date no therapeutic cannabinoid has been developed that is devoid of psychoactive effects such as sedation, loss of short-term memory, and disorientation. In addition, no high-affinity antagonist exists with which important biochemical and pharmacological data concerning the cannabinoid receptor could be obtained. To address the cannabinoid receptor as a potential site for therapeutic pharmacological intervention, additional information concerning cannabinoid receptor- ligand interactions is required. The specific aims of this Biochemistry section of the Program Project are: 1. Characterization of covalent affinity ligands: A) Characterize the binding of novel cannabinoid ligands to wild-type cannabinoid receptors in baculovirus-infected Sf9 cell membranes and, B) Determine the site(s) of receptor-ligand interaction in wild-type receptors by analysis of covalently labeled proteolyzed receptor peptides. 2. Characterization of cannabinoid receptor chimeras: A) Characterize the binding of cannabinoid ligands to cannabinoid receptor chimeras expressed in Sf9 membranes. B) Characterize the functional properties of wild-type and chimeric receptors when reconstituted with G proteins in defined phospholipid vesicles.